Invasive Intraductal Papillary Mucinous Neoplasm Research Articles

ASO Visual Abstract: Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with De Novo Pancreatic Adenocarcinoma.

ASO Visual Abstract: Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with De Novo Pancreatic Adenocarcinoma.

Prognostic performance of microscopic size measurements in small invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas.

Small invasive carcinomas arising in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can present as multiple, small foci. In such cases, there is no clear optimal measurement method for determining the invasive size for tumour staging and prognostication. In all, 117 small invasive IPMNs (size of largest invasive component ≤2 cm) from seven institutions (2000-2016) were reviewed, and all individual foci of invasive carcinoma were measured. T stages (AJCC 8th edition) based on the largest single focus size (LS), average size of all foci (AS), and total sum of all foci (TS) were examined in association with clinicopathologic parameters and patient outcomes. The cohort comprised IPMNs with invasive tubular-type (n = 82, 70%) and colloid-type (n = 35, 30%) carcinomas. The mean LS, AS, and TS were 0.86, 0.71, and 1.32 cm, respectively. Based on the LS, AS, and TS, respectively, 48, 65, and 39 cases were classified as pT1a; 22, 18, and 11 cases as pT1b; and 47, 34, and 50 cases as pT1c. Higher pT stages based on all measurements were significantly associated with small vessel, large vessel, and perineural invasion (P < 0.05). LS-, AS-, and TS-based pT stages were not significantly associated with recurrence-free survival (RFS) or overall survival (OS) by univariate or multivariate analyses. However, among tubular-type carcinomas, higher LS-, AS-, and TS-based pT stages trended with lower RFS (based on 1-, 3-, and 5-year survival rates). All microscopic measurement methods were most predictive of RFS and OS using a 1.5-cm cutoff, with LS significantly associated with both RFS and OS by univariate and multivariate analysis. For invasive tubular-type carcinomas arising in IPMN, microscopic size-based AJCC pT stages were not significant predictors of patient outcomes. However, for LS, a size threshold of 1.5 cm was optimal for stratifying both RFS and OS. The AJCC 8th ed. may not be applicable for stratifying small invasive IPMNs with colloid-type histology that generally portend a more favourable prognosis.

O77: Invasive intraductal oncocytic papillary neoplasms (IOPN) and adenocarcinomas arising from Intraductal papillary mucinous neoplasms (IPMN): adjuvant chemotherapy, patterns of recurrence and survival

Abstract Introduction Invasive intraductal oncocytic papillary neoplasms (IOPNs) are extremely rare and are increasingly being recognised as their own entity, distinct from intraductal papilliary mucinous neoplasism subtypes (IPMN). Their clinicopathologic behaviour, recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown compared to adenocarcinomas arising from IPMN but were investigated in the present study. Methods Patients undergoing pancreatic resection between 2010-2020 for invasive IOPNs and adenocarcinoma arising from IPMNs were identified retrospectively from 18 academic pancreatic centers worldwide. Survival analyses were conducted to compare outcome measures between IOPNs and IPMN precursor epithelial subtypes and invasive components. Results Of the 459 patients with invasive IOPN/IPMNs, 20 patients had an invasive IOPN (median age,69; male,n=11), the majority of which were in the pancreatic head (75%) and underwent either a Whipples procedure (40%) or PPPD (35%). After a median follow-up of 6 years, 45% of invasive IOPNs developed recurrence (1-year,30.0%; 5-year,69.2%) and 40% survived follow-up (2-year survival 55.0%, 5-year survival, 30.8%). Recurrence rates and survival of invasive IOPNs were higher than colloid IPMNs (n=64) (p=0.031 and p=0.007) and comparable with ductal IPMNs (n=331) as well as gastric (n=54) and pancreatobiliary (n=111) IPMN subtypes. Invasive IOPN had significantly lower cancer-specific survival compared to colloid carcinomas (p&amp;lt;0.001). Adjuvant chemotherapy did not improve rates of recurrence in invasive IOPN and IPMN subtypes (p&amp;gt;0.05). Conclusions Invasive IOPNs are more aggressive than previously suspected and should be regarded as their own entity. Adjuvant chemotherapy does not reduce rates of recurrence regardless of neoplasm type.

Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with de Novo Pancreatic Adenocarcinoma

BackgroundThe management of invasive intraductal papillary mucinous cystic neoplasm (I-IPMN) does not differ from de novo pancreatic ductal adenocarcinoma (PDAC); however, I-IPMNs are debated to have better prognosis. Despite being managed similarly to PDAC, no data are available on the response of I-IPMN to neoadjuvant chemotherapy.MethodsAll patients undergoing pancreatic resection for a pancreatic adenocarcinoma from 2011 to 2022 were included. The PDAC and I-IPMN cohorts were compared to evaluate response to neoadjuvant therapy (NAT) and overall survival (OS).ResultsThis study included 1052 PDAC patients and 105 I-IPMN patients. NAT was performed in 25% of I-IPMN patients and 65% of PDAC patients. I-IPMN showed a similar pattern of pathological response to NAT compared with PDAC (p = 0.231). Furthermore, positron emission tomography (PET) response (71% vs. 61%; p = 0.447), CA19.9 normalization (85% vs. 76%, p = 0.290), and radiological response (32% vs. 37%, p = 0.628) were comparable between I-IPMN and PDAC. A significantly higher OS and disease-free survival (DFS) of I-IPMN was denoted by Kaplan–Meier analysis, with a p-value of < 0.001 in both plots. In a multivariate analysis, I-IPMN histology was independently associated with lower risk of recurrence and death.ConclusionsI-IPMN patients have a longer OS and DFS after surgical treatment when compared with PDAC patients. The more favorable oncologic outcome of I-IPMNs does not seem to be related to early detection, as I-IPMN histological subclass is independently associated with a lower risk of disease recurrence. Moreover, neoadjuvant effect on I-IPMN was non-inferior to PDAC in terms of pathological, CA19.9, PET, and radiological response and thus can be considered in selected patients.

Abstract B072: SMAD4 loss allows progression from benign to malignant disease in intraductal papillary mucinous neoplasms

Abstract As increasing numbers of MRIs and other scans are ordered for unrelated diseases, more and more people are being diagnosed with cystic neoplasms of the pancreas. While many or most of these will likely remain benign, intraductal papillary mucinous neoplasms (IPMNs) have a risk of progression to cancer and IPMN is now recognized as another precursor to pancreatic ductal adenocarcinoma. We are investigating the mechanisms by which IPMNs progress from benign to malignant disease in order to identify markers of progression and targets to block that progression. We found that loss of SMAD4 in conjunction with Krasmutation leads to IPMN that quickly becomes invasive in a mouse model. Examining human IPMN tissues, we found that only one in 46 benign IPMN tumors lacked detectable SMAD4 protein. Among 19 cases of invasive IPMNs, the sites of active invasion were SMAD4 negative in 7 cases, nuclear negative/cytoplasm positive in 3 cases (suggesting no active canonical signaling), and a mix of positive and negative cells in 3 cases, implicating complete or partial loss of SMAD-mediated signaling in 68% of actively invading cells. In order to understand how SMAD signaling blocks progression to invasion, we are examining cell lines from a benign mouse model of IPMN. While these lines do not have endogenous TGF beta signaling, they are capable of responding to exogenous TGF beta, suggesting that TGF beta-related ligands may be supplied by the tumor microenvironment rather than the tumor cells themselves. We are currently determining how different TGF beta family members contribute to regulation of growth and invasion in these cells. In summary, loss of the tumor suppressor SMAD4 allows an otherwise benign disease to progress to invasive cancer. Citation Format: Anna L. Means, Hannah Yoo, Quoc-Huy Trinh, Roshini Thiagarajan, Jinghuan Zi, Frank L. Revetta, Marcus C. Tan, Kathleen E. DelGiorno, Mary K. Washington. SMAD4 loss allows progression from benign to malignant disease in intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B072.

Abstract A028: Multiomic modelling of pancreatic IPMN stroma reveals distinct tertiary lymphoid structure distribution: Mapping the transcriptomic landscape via regional bulk, single-cell and subcellular approaches

Abstract Background Intraductal Papillary Mucinous Neoplasms (IPMN) remain the largest subtype of cystic pancreatic cancer precursors. Cancer risk has been observed to vary between histological grades and histological subtypes. Spatial characterisation has revealed variation in immune cell distribution disease subtypes. Methods A cohort of 14 surgically resected IPMN tumors across a range of histological grades (Low-grade LG, high-grade HG and invasive IPMN cancers IPMN-PDAC) and subtypes (gastric, intestinal, pancreaticobiliary) underwent multimodal spatial interrogation. After expert histopathological annotation; tissue sections underwent regional whole transcriptome analysis with TempO-seq and 10x Visium. Extensive region analysis with NanoString GeoMx employing segmentation using staining for epithelium (PanCK) fibroblast stroma (aSMA) was performed. A tissue microarray was then constructed, and representative cores underwent single-cell and subcellular spatial transcriptomic analysis with NanoString CosMx. Raw count data and digital images were exported and analysed using Seurat, Giotto, SPATA2 and custom R pipelines. Region deconvolution, Harmony integration, Leiden Clustering, Gene Set Enrichment Analysis, Trajectory Mapping, and Moran’s I Analysis were performed. Results TempO-seq revealed up-regulation of canonical oncogene expression in all IPMN-PDAC cases as compared to LG and HG IPMN. There were no statistically significant differences in expression comparing LG and HG IPMN lesions. Visium differential gene expression and clustering models identified cancer epithelium, stroma and lymphatic components that correlated with histopathological annotations. Immune cell rich spots were identified via gene ontology of top 50 marker genes. The spatial trajectory of B-cell expression signatures in IPMN-PDAC showed greater concentration and less variability than HG tumors, Moran’s I -0.34 vs 0.12 (P = 0.021). B-cells in HG IPMN were showed greater concentration and less variability than LG IPMN, Moran’s I -0.15 vs 0.02 (P=0.05). Much of this concentration was in identified lymphoid aggregates or tertiary lymphoid structures. The spatial trajectory of T-cell expression. The spatial trajectory of macrophage expression showed greater concentration and less variability than in LG and HG tumors. GeoMx analysis of stromal regions identified up regulation of B cell signatures in IPMN PDAC and HG IPMN when compared to LG IPMN. Markers associated with TLS formation were found to be significantly upregulated including CXCL13, CXCR5 and LAMP3. Pancreaticobiliary subtypes were found to have the least concentrated B-cell distribution across subtypes. Conclusions Immune cell composition was found to vary across histological grades and subtypes of IPMN. A paradoxical relationship was observed between T-cell infiltrates and B-cell and macrophage populations. The greater proportion of tertiary lymphoid structures, and high levels of TLS specific gene expression, may indicate a propensity for b-cell activation in IPMN tumors which progress to malignancy. Citation Format: Andrew J. Cameron, Assya Legrini, Colin S. Wood, Craig Nourse, Yoana Doncheva, Claire Kennedy Dietrich, Colin Nixon, Jennifer Hay, Fraser Duthie, Pawel Herzyk, Jennifer Morton, Nigel B. Jamieson. Multiomic modelling of pancreatic IPMN stroma reveals distinct tertiary lymphoid structure distribution: Mapping the transcriptomic landscape via regional bulk, single-cell and subcellular approaches [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A028.

Margin-negative minimally invasive pancreatoduodenectomy following FOLFIRINOX neoadjuvant chemotherapy in invasive intraductal papillary mucinous neoplasm of pancreas: a case report.

This study shows a case of neoadjuvant chemotherapy application for the management of a 34-year-old male patient diagnosed with invasive intraductal papillary mucinous neoplasm (IPMN), for which curative margin-negative resection initially seemed challenging. Five cycles of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were administered preoperatively, resulting in a significant reduction of the intraductal mass size and deformity of the main vessels. The patient subsequently underwent a successful robotic pylorus-preserving pancreatoduodenectomy. Postoperatively, the patient received adjuvant chemotherapy with FOLFIRINOX, and after 5 months, showed no signs of tumor recurrence or specific complications. These findings suggest that neoadjuvant therapy can be a potentially effective strategy even in advanced invasive IPMN. Further research is necessary to establish guidelines for its application.

Serum elastase-1 predicts malignancy in intraductal papillary mucinous neoplasm of the pancreas

BackgroundThe indication for surgical resection of intraductal papillary mucinous neoplasms (IPMNs) is defined by imaging features, such as mural nodules. Although carbohydrate antigen (CA) 19-9 was selected as a parameter for worrisome features, no serum biomarkers were considered when deciding on surgical indications in the latest international consensus guideline. In this study, we assessed whether clinical factors, imaging findings, and serum biomarkers are useful in predicting malignant IPMNs. MethodsA total of 234 resected IPMN cases in Chiba University Hospital from July 2005 to December 2021 were retrospectively analyzed. ResultsAmong the 234 patients with resected IPMNs diagnosed by preoperative imaging, 117 were diagnosed with malignant pathologies (high-grade dysplasia and invasive IPMNs) according to the histological classification. In the multivariate analysis, cyst diameter ≥30 mm; p = 0.035), enhancing mural nodules on multidetector computed tomography (≥5 mm; p = 0.018), and high serum elastase-1 (≥230 ng/dl; p = 0.0007) were identified as independent malignant predictors, while CA19-9 was not. Furthermore, based on the receiver operator characteristic curve analyses, elastase-1 was superior to CA19-9 for predicting malignant IPMNs. Additionally, high serum elastase-1 levels (≥230 ng/dl; p = 0.0093) were identified as independent predictors of malignant IPMNs in patients without mural nodules on multidetector computed tomography (MDCT) in multivariate analysis. ConclusionThe serum elastase-1 level was found to be a potentially useful biomarker for predicting malignant IPMNs.

Inadequacy of the eighth edition of the American Joint Committee on Cancer pancreatic cancer staging system for invasive carcinoma associated with premalignant lesions in the pancreas: an analysis using the National Cancer Database

BackgroundInvasive carcinomas arising from premalignant lesions are currently staged by the same criteria as conventional pancreatic ductal adenocarcinoma. MethodsClinicopathologic information and survival data were extracted through a thorough search of histology codes from National Cancer Database (2006–2016). A total of 723 patients with invasive intraductal papillary mucinous neoplasm and mucinous cystic neoplasm were analyzed. ResultsThe median age was 67 years, and 351 patients (48.5%) were male. There were 212 (29.3%), 232 (32.1%), 272 (37.6%), and 7 (1.0%) patients with T1, T2, T3, and T4 classification. Extrapancreatic extension (EPE) was present in 284 (39.3%). Age (HR = 1.504, 95% CI 1.196–1.891), R1 or R2 resection (HR = 1.585, 95% CI 1.175–2.140), and EPE (HR = 1.598, 95% CI 1.209–2.113) were independent prognostic factors for overall survival. Size criteria did not significantly affect survival. The median survival was 115.9 months for patients without EPE, compared to 34.2 months for those with EPE. EPE discriminated survival better than tumor size. DiscussionThe T classification of the eighth edition AJCC staging system is not adequate for invasive carcinomas associated with premalignant lesions of the pancreas. They merit a separate, dedicated staging system that uses appropriate prognostic factors.

Predictors of malignant intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) is the most common pancreatic cystic neoplasm with a tendency to malignancy,and the 5-year survival rate of patients with invasive IPMN is less than 40%. Therefore,early detection of malignant cases and surgical intervention will significantly improve patient outcomes. The clinical guidelines recommended risk factors for IPMN malignancy according to imaging characteristics,clinical manifestations and serum tumor markers,among which dilation of the main pancreatic duct≥10 mm,the presence of solid components or enhanced mural nodules,and obstructive jaundice were recognized as high-risk factors. However,clinical practice has shown that the risk factors recommended by the current guidelines are not highly accurate in predicting IPMN malignancy,and the main problem is that the guidelines are less specific and allow follow-up cases to undergo unnecessary surgical resection. In recent years,the development of new technologies and methods such as genomics,radiomics,and artificial intelligence has greatly promoted the research progress of IPMN. Endoscopic ultrasound-guided fine needle aspiration of cystic fluid combined with molecular detection such as DNA and RNA,as well as radiomics combined with machine learning modeling,have shown superiority in improving the prediction accuracy of malignant IPMN,and will become an important tool to assist the diagnosis and treatment of IPMN in the future.

Clinical characteristics and survival prediction of surgical patients with invasive pancreatic cystic neoplasm: a large retrospective study over two decades

PurposesInvasive pancreatic cystic neoplasms (iPCNs) are an uncommon and biologically heterogeneous group of malignant neoplasms. We aimed to investigate the clinicopathological characteristics of iPCN patients and to develop nomograms for individual survival prediction after radical surgery.MethodsData of patients diagnosed with iPCN and pancreatic ductal adenocarcinoma (PDAC) between 2000 and 2018 from the SEER database were retrieved. The differences in clinical outcomes were evaluated using the Kaplan–Meier analysis. Nomograms were proposed based on the Cox regression model and internally validated by C-index, area under the curve (AUC) value, and calibration plot.ResultsA total of 7777 iPCN patients and 154,336 PDAC patients were enrolled. Most neoplasms were advanced, with 63.1% at stage IV. The 3-year overall survival (OS) and cancer-specific survival (CSS) rates in surgical patients were as follows: 45.7% and 50.1% for invasive intraductal papillary mucinous neoplasm (IPMN), 54.8% and 59.3% for invasive mucinous cystic neoplasm (MCN), 97.8% and 98.2% for invasive solid pseudopapillary neoplasm (SPN), 88.9% and 88.9% for invasive serous cystic neoplasm (SCN), and 27.3% and 30.5% for PDAC. Subgroup analyses showed no clinical benefit from chemotherapy or radiotherapy in lymph node-negative iPCN patients who underwent surgery. The following variables associated with OS and CSS were identified: age, race, chemotherapy, radiotherapy, histologic type, pathological grade, regional nodes examined, and T, N, and M stage. The nomograms had good discrimination and calibration by internal validation, with an AUC value of 0.800 for 3-year OS and 0.814 for 3-year CSS.ConclusionOur study showed that the prognosis of iPCN patients was significantly better than PDAC patients. The proposed nomograms demonstrated substantially better discrimination and calibration.

N-glycosylation in non-invasive and invasive intraductal papillary mucinous neoplasm

Intraductal papillary mucinous neoplasms (IPMNs), often found incidentally, are potentially malignant cystic tumors of the pancreas. Due to the precancerous nature, IPMNs lacking malignant features should be kept on surveillance. The follow-up relies on magnetic resonance imaging, which has a limited accuracy to define the high-risk patients. New diagnostic methods are thus needed to recognize IPMNs with malignant potential. Here, aberrantly expressed glycans constitute a promising new area of research. We compared the N-glycan profiles of non-invasive IPMN tissues (n = 10) and invasive IPMN tissues (n = 10) to those of non-neoplastic pancreatic controls (n = 5) by matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry. Both IPMN subgroups showed increased abundance of neutral composition H4N4 and decrease in H3N5F1, increase in sialylation, and decrease in sulfation, as compared to the controls. Furthermore, invasive IPMN showed an increase in terminal N-acetylhexosamine containing structure H4N5, and increase in acidic complex-type glycans, but decrease in their complex fucosylation and sulfation, as compared to the controls. In conclusion, the N-glycan profiles differed between healthy pancreatic tissue and non-invasive and invasive IPMNs. The unique glycans expressed in invasive IPMNs may offer interesting new options for diagnostics.

Epidemiology and outcome of individuals with intraductal papillary neoplasms of the bile duct.

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare distinct subtype of precursor lesions of biliary carcinoma. IPNB is considered to originate from luminal biliary epithelial cells, typically displays mucin-hypersecretion or a papillary growth pattern, and results in cystic dilatation[1]. IPNB develops anywhere in the intrahepatic and extrahepatic biliary tracts, and can occur in various pathological stages from low-grade dysplasia to invasive carcinoma. IPNBs have similar phenotypic changes in the occurrence and development of all subtypes, and the prognosis is significantly better than that of traditional (non-papillary) cholangiocarcinoma. To evaluate the clinicopathological features of IPNB to provide evidence-based guidance for treatment. Invasive IPNB, invasive intraductal papillary mucinous neoplasm of the pancreas (IPMN), and traditional cholangiocarcinoma data for affected individuals from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Annual percentage changes (APCs) in the incidence and incidence-based (IB) mortality were calculated. We identified the independent predictors of overall survival (OS) and cancer-specific survival (CSS) in individuals with invasive IPNB. The incidence and IB mortality of invasive IPNB showed sustained decreases, with an APC of -4.5% (95%CI: -5.1% to -3.8%) and -3.3% (95%CI: -4.1% to -2.6%) (P < 0.001), respectively. Similar decreases in incidence and IB mortality were seen for invasive IPMN but not for traditional cholangiocarcinoma. Both OS and CSS for invasive IPNB were better than for invasive IPMN and traditional cholangiocarcinoma. A total of 1635 individuals with invasive IPNB were included in our prognosis analysis. The most common tumor sites were the pancreaticobiliary ampulla (47.9%) and perihilar tract (36.7%), but the mucin-related subtype of invasive IPNB was the main type, intrahepatically (approximately 90%). In the univariate and multivariate Cox regression analysis, age, tumor site, grade and stage, subtype, surgery, and chemotherapy were associated with OS and CSS (P < 0.05). Incidence and IB mortality of invasive IPNB trended steadily downward. The heterogeneity of IPNB comprises site and the tumor's mucin-producing status.

Microvessel findings of invasive intraductal papillary mucinous neoplasm of the pancreas observed using the magnifying narrow-band imaging system

Microvessel findings of invasive intraductal papillary mucinous neoplasm of the pancreas observed using the magnifying narrow-band imaging system

Pre-emptive resection for intraductal papillary mucinous neoplasia – Long-term outcome is similar between non-invasive and early invasive lesions in a tertiary single center

BackgroundPre-emptive resection for intraductal papillary mucinous neoplasm (IPMN) aims to reduce the risk before invasive transformation has taken place. Pancreatic resections are highly associated with major morbidity and mortality. Long-term overall survival (OS) after resection for invasive IPMN (inv-IPMN) in early stages is favorable. Comparison of long-term OS for resected non-invasive IPMN and early staged inv-IPMN is poorly delineated. This study aims to compare outcomes for resected non-invasive IPMN and T1-staged inv-IPMN. MethodsAll patients ≥18 years of age resected for IPMN up to stage T1 at Karolinska University Hospital between 2008 and 2020 were included. Two-year OS were compared between groups by chi-squared test, and 5-year OS was estimated using Kaplan-Meier method. Covariates associated with death was assessed in multivariable Cox regression model. ResultsWe included 284 patients, 264 (93%) non-invasive IPMN and 20 (7%) T1-staged inv-IPMN. Dysplasia of low grade (LGD) and high grade, i.e., tumor in situ (Tis) were present in 190 (67%) and 75 (26%) patients respectively. The 2-year OS for the entire cohort was 96%, and there were no differences between non-invasive and inv-IPMN (96% vs 92%, p = 0.203), nor between IPMN with LGD and Tis-T1b-staged IPMN (96% vs 95%, p = 0.734). ConclusionTwo thirds of the specimen from pre-emptive resections were of LGD and did not involve superior OS than in situ or early cancer. Due to high complication burden, efforts should be made to avoid resection when LGD is probable and rather identify more accurate predictors for surgery.

Comparison of Invasive Pancreatic Ductal Adenocarcinoma versus Intraductal Papillary Mucinous Neoplasm: A National Cancer Database Analysis

Current evidence on overall survival (OS) between invasive pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) is limited to single-center reports. We aimed to compare the characteristics, management, and OS of invasive PDAC vs. IPMN using a national United States (US) database. Invasive PDAC or IPMN adult (≥18 years) patients were identified in the National Cancer Database (2004-2016). OS was assessed with the Kaplan-Meier method and the stratified log-rank test. We included 101,190 patients (100,834 PDAC, 356 IPMN). A higher proportion of PDAC vs. IPMN patients had clinical N1 (36.8% vs. 15.7%, p < 0.001) and M1 disease (41.2% vs. 5.9%, p < 0.001). A lower proportion of PDAC patients underwent surgery (25.5% vs. 80.3%, p < 0.001), but a higher proportion received chemotherapy (65.4% vs. 46.1%, p < 0.001) or radiation (25.3% vs. 20.5%, p = 0.04). A higher proportion of surgical patients with PDAC vs. IPMN underwent margin-positive resection (23.0% vs. 14.0%, p = 0.001). The median OS for PDAC vs. IPMN was 8.3 vs. 33.4 months. In the stratified analysis for N0M0 disease, the median OS for PDAC vs. IPMN was 12.8 vs. 43.3 months, for N1M0, it was 11.5 vs. 17.0 months, while for M1, it was 4.0 vs. 7.0 months. In both diagnoses, surgery yielded improved OS, while stratified analysis in the surgical cohort demonstrated similar findings. Invasive PDAC is more aggressive than invasive IPMN, yet in the case of metastasis, OS is equally poor. Excellent long-term OS is achievable with surgical resection in highly selected cases, and efforts should focus on facilitating surgical treatment.

Outcome after surgery for invasive intraductal papillary mucinous neoplasia compared to conventional pancreatic ductal adenocarcinoma – A Swedish nationwide register-based study

BackgroundThe clinical importance of intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Long-term survival after resection for invasive IPMN (inv-IPMN) compared to conventional pancreatic ductal adenocarcinoma (PDAC) is not thoroughly delineated. ObjectiveThis study, based on the Swedish national pancreatic and periampullary cancer registry aims to elucidate the outcome after resection of inv-IPMN compared to PDAC. MethodsAll patients ≥18 years of age resected for inv-IPMN and PDAC in Sweden between 2010 and 2019 were included. Clinicopathological variables were retrieved from the national registry. The effect on death was assessed in two multivariable Cox regression models, one for patients resected 2010–2015, one for patients resected 2016–2019. Median overall survival (OS) was estimated using the Kaplan-Meier method. ResultsWe included 1909 patients, 293 inv-IPMN and 1616 PDAC. The most important independent predictors of death in multivariable Cox regressions were CA19-9 levels, venous resection, tumour differentiation, as well as T-, N-, M-stage and surgical margin. Tumour type was an independent predictor for death in the 2016–2019 cohort, but not in the 2010–2015 cohort. In Kaplan-Meier survival analysis, inv-IPMN was associated with longer median OS in stage N0-1 and in stage M0 compared to PDAC. However, in stage T2-4 and stage N2 median OS was similar, and in stage M1 even shorter for inv-IPMN compared to PDAC. ConclusionIn this population-based nationwide study, outcome after resected inv-IPMN compared to PDAC is more favourable in lower stages, and similar to worse in higher.

Are intratumoral microbiota involved in the progression of intraductal papillary mucinous neoplasms of the pancreas?

BackgroundMicrobiota have been reported to influence the development of various gastrointestinal neoplasms through the mechanism of sustained inflammation; however, few data are available regarding their influence on intraductal papillary mucinous neoplasms. The aim of this study was to assess the association between specific microbiota and the clinicopathologic characteristics of intraductal papillary mucinous neoplasms of the pancreas. MethodsDNA was extracted from formalin-fixed, paraffin-embedded samples of 30 patients who underwent pancreatectomy for intraductal papillary mucinous neoplasm, and polymerase chain reaction was used to create sequence libraries using the primer set for the V3 and V4 region of 16S recombinant DNA. Filtered sequence reads were then processed into operational taxonomic units with a 97% identity threshold and the relative abundance of bacteria compared between the 2 groups using operational taxonomic units. ResultsThere was a trend toward fewer Firmicutes and more Proteobacteria and Fusobacteria in the relative abundance of main duct operational taxonomic units than in branch duct operational taxonomic units. The relative abundances of Bacteroidetes (P < .01) and Fusobacteria (P = .04) were significantly higher in invasive intraductal papillary mucinous neoplasms than in noninvasive intraductal papillary mucinous neoplasms. The relative abundance of the intestinal type was significantly lower in Firmicutes than the relative abundance of the nonintestinal type (P = .04). Notably, main duct operational taxonomic units with the intestinal subtype were affected by increased proportions of Proteobacteria and Fusobacteria, and Fusobacteria were abundant in the intestinal type of invasive main duct operational taxonomic units. ConclusionIntratumoral microbiota may be involved in the progression of operational taxonomic units.

Two Cases of Duodenal Neuroendocrine (Carcinoid) Tumor Concurrent with Invasive Gastric Adenocarcinoma and Pancreatic Intraductal Papillary Mucinous Neoplasm

Abstract Introduction/Objective Neuroendocrine (carcinoid) tumors of the duodenum are extremely rare and account for only 2-4% of gastrointestinal tract neuroendocrine tumors. We report two cases of incidentally discovered duodenal neuroendocrine tumor which respectively occurred in a patient with invasive gastric adenocarcinoma and in a patient with pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods/Case Report The first case involved a 60-year old male who presented with melena and symptomatic anemia and was found on EGD to have a large circumferential mass at the gastric antrum/pylorus, which was revealed to be an invasive gastric adenocarcinoma on biopsy. At the time of distal gastrectomy for this malignancy, a concurrent, 0.6 cm-sized, low grade neuroendocrine tumor was incidentally discovered at the duodenal margin. The duodenal tumor consisted of nests and trabeculae of monotonous cells with ovoid/round nuclei, finely speckled “salt and pepper” chromatin, and low mitotic rate (&amp;lt; 2 mitoses/2 mm2), and invaded only into submucosa. The tumor cells were strongly and diffusely positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, positive for CK7 and CDX2, negative for CK20, and with low Ki67 proliferation index (&amp;lt; 3%). The second case involved a 69-year old female who presented with epigastric pain and was found on abdominal CT to have a 4 cm-sized cystic mass in the pancreatic head. While biopsy of the pancreatic mass revealed an IPMN, a separate biopsy of an incidentally discovered, 1 cm-deep ulcer in the duodenum bulb revealed a low-grade neuroendocrine tumor with similar morphologic features, mitotic rate, and immunohistochemical staining pattern as the prior case while also negative for IMP3 stain. The patient had normal serum gastrin and urine HIAA levels, but elevated serum chromogranin-A levels. Results (if a Case Study enter NA) NA. Conclusion Duodenal carcinoids are rare (1-3% of primary duodenal tumors) and are mostly non-functional and unifocal. The duodenum is also the least common site (2-4%) for GI tract neuroendocrine tumors. The pathophysiology of these tumors is still poorly understood, with the majority occurring sporadically and a minority in the setting of hereditary cancer syndromes. This report documents two very rare instances of duodenal neuroendocrine tumor incidentally discovered with invasive gastric adenocarcinoma and pancreatic IPMN.

Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas.

The development of neural structures within tumors is now considered vital for carcinogenesis. However, the time course of this development in human pre-invasive neoplasia has been incompletely described. Therefore, we performed a detailed analysis of nerves across the neoplastic spectrum in resected intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Histology and multiplexed immunochemistry demonstrated that nerve density increased from low-grade (LG) to high-grade dysplasia (HG) but did not further increase once invasive IPMN (INV IPMN) was present. Higher nerve density correlated with increasing expression of nerve growth factor (NGF) by the tumor cells. Intra-tumoral nerves were immature and lacked markers of sympathetic, parasympathetic, and sensory lineages. Here, we show for the first time the presence of neural precursor cells (NPCs) within the stroma of pancreatic tumors. The density of these doublecortin (DCX)-positive NPCs increased from LG to HG, but not from HG to INV IPMN. We conclude that peak neural density of tumors is reached in high-grade dysplasia (often termed carcinoma in situ) rather than after invasion. These findings suggest that nerve-tumor interactions are important in IPMN progression and may serve as the basis for future mechanistic studies and novel therapeutic modalities. © 2022 The Pathological Society of Great Britain and Ireland.